Aqueous-based pharmaceutical composition

ABSTRACT

An aqueous pharmaceutical composition which is capable of being sprayed into the nasal cavity of an individual and which comprises: (A) a pharmaceutically effective amount of solid particles of medicament which is effective in treating a bodily condition by virtue of its being present on the mucosal surfaces of the nasal cavity; and (B) a suspending agent in an amount effective to maintain said particles dispersed uniformly in the composition and to impart to the composition the following thixotropic properties: (i) the viscosity of the position in unsheared form is relatively high, with the composition being in gel-like form; (ii) as the composition is subjected to shear (shaken) in preparation for spraying, the viscosity of the composition becomes relatively low and such that the composition in the form of a mist flows readily into the nasal passages for deposit on the mucosal surfaces of the nasal cavity; and (iii) in deposited form on the mucosal surfaces, the viscosity of the composition is relatively high and such that it resists being cleared from the mucosal surfaces by the inherent mucocillary forces which are present in the nasal cavity, a method of use of the composition and a method for preparation of the composition, including in preferred form the use of anti-inflammatory steroid, for example, triamcinolone acetonide, and an odorless form of the composition.

FIELD OF THE INVENTION

This invention relates to an aqueous-based pharmaceutical composition.More particularly, this invention relates to an aqueous compositioncontaining a medicament that is effective in treating an abnormal bodilycondition by virtue of its being present on the surfaces of the mucosawhich line the nasal cavities.

The field of the present invention is described initially in connectionwith the treatment of particular forms of rhinitis, that is, an abnormalbodily condition that involves inflammation of the mucous membrane ofthe nose. It should be understood that the invention has broaderapplicability, as will be described below.

An estimated forty million Americans suffer from seasonal and perennialallergic rhinitis. Many more millions of individuals suffer from thiscondition worldwide. Symptoms of seasonal and perennial allergicrhinitis include nasal itch, congestion, runny nose, sneezing and wateryeyes. Seasonal allergic rhinitis is commonly known as "hay fever". It iscaused by allergens which are present in the air at specific times ofthe year. Tree pollens in the springtime of the year are examples ofsuch allergens. Perennial allergic rhinitis is caused by allergens whichare present in the environment year-round. Examples of such allergensare dust mites, mold, mildew, and pet dander.

It is known to treat such forms of rhinitis with medicaments such as,for example, steroidal anti-inflammatory agents. Triamcinolone acetonideis an example of a widely used steroidal anti-inflammatory agent. Suchan agent is generally used by spraying it into the nasal passages of thehuman patient where it deposits on surfaces of the mucosa which line thenasal cavities. In this position, the medicament exerts itspharmacological action as it is in contact with bodily tissues andinteracts with steroid receptors.

For maxim um effectiveness, a pharmaceutical composition containing theaforementioned type of medicament must have a combination of desiredproperties. For example, the nature of the pharmaceutical compositioncontaining the medicament should be such that the medicament isdelivered readily to all portions of the nasal cavities (the targettissues) where it performs its pharmacological function. In addition,the medicament should remain in contact with the target tissues forrelatively long periods of time. The longer the medicament remains incontact with the target tissues, the greater the opportunity for themedicament to perform its function. In order to remain in contact withthe target tissues, the medicament must be capable of resisting thoseforces in the nasal passages that function to remove particles from thenose. Such forces, referred to as "mucocillary clearance", arerecognized as being extremely effective in removing particles from thenose in a rapid manner, for example, within 10-30 minutes from the timethe particles enter the nose.

Other desired characteristics of the pharmaceutical composition are thatit not contain ingredients which cause the user discomfort, that it havesatisfactory stability and shelf-life properties, and that it notinclude constituents that are considered to be detrimental to theenvironment, for example, ozone depletors.

The present invention relates to a pharmaceutical composition which hasa combination of properties that make it particularly effective andsuitable for relieving abnormal bodily conditions that can be treated bydepositing the composition on the surface of the mucosa which line thenasal passages.

Reported Developments

The following patents disclose pharmaceutical compositions which containvarious types of medicaments, including medicaments which function totreat an abnormal bodily condition by virtue of the medicament's beingpresent on the mucosal surfaces of the nasal cavities, U.S. Pat. Nos.3,780,176; 3,809,294; 3,897,779; 4,405,598; 4,250,163; 4,294,829;4,304,765; 4,407,792; 4,432,964; 4,443,440; 4,478,818; and 5,439,670.

In contrast to compositions described in the aforementioned patents, thepharmaceutical composition of the present invention is aqueous based.

SUMMARY OF THE INVENTION

In accordance with the present invention, there is provided an aqueouspharmaceutical composition which is capable of being sprayed into thenasal cavity of an individual and which comprises: (A) apharmaceutically effective amount of solid particles of medicament whichis effective in treating a bodily condition by virtue of its beingpresent on the mucosal surfaces of the nasal cavity; and (B) asuspending agent in an amount effective to maintain said particlesdispersed uniformly in the composition and to impart to the compositionthe following thixotropic properties: (i) the viscosity of the positionin unsheared form is relatively high, with the composition being ingel-like form; (ii) as the composition is subjected to shear (shaken) inpreparation for spraying, the viscosity of the composition becomesrelatively low and such that the composition in the form of a mist flowsreadily into the nasal passages for deposit on the mucosal surfaces ofthe nasal cavity; and (iii) in deposited form on the mucosal surfaces,the viscosity of the composition is relatively high and such that itresists being cleared from the mucosal surfaces by the inherentmucocillary forces which are present in the nasal cavity.

In preferred form, the medicament comprises an anti-inflammatorysteroid, most preferably triamcinolone acetonide. Also in preferredform, the composition of the present invention is odorless and includesa quaternary ammonium compound, preferably benzalkonium chloride, and achelating agent, preferably disodium ethylenediamine tetraacetate(EDTA).

Another aspect of the present invention comprises a method for applyingsolid particles of a medicament to the mucosal surfaces of the nasalcavities comprising spraying a dose of an aqueous pharmaceuticalcomposition containing said medicament into each of the nasal cavities,said dose containing a pharmaceutically effective amount of saidmedicament, said composition including also a suspending agent in anamount which is effective in maintaining said particles disperseduniformly in the composition and in imparting to the compositionthixotropic properties such that pharmaceutically effective amounts ofthe medicament are deposited at least on each of the mucosal surfaces ofthe anterior regions of the nose, the frontal sinus and the maxillarysinuses and on each of the mucosal surfaces which overlie the turbinatescovering the conchas and such that portions of said amounts are retainedon each of said mucosal surfaces for at least about an hour.

In preferred form, the composition is applied to the nasal cavities byspraying utilizing a precompression pump.

Still another aspect of the present invention comprises a method forpreparing an aqueous pharmaceutical composition comprising a medicamentin the form of solid particles, a dispersing agent for wetting saidparticles, and a suspending agent for maintaining said particlessubstantially uniformly dispersed in the composition and for impartingto the composition thixotropic properties comprising: (A) forming anaqueous solution of the dispersing agent and combining the solution withthe solid particles to form a suspension of the particles; (B) addingthe suspending agent to an aqueous acidic solution to form a thixotropicsuspension; and (C) combining each of the suspensions by introducing oneof the suspensions into the bottom of the other suspension.

In preferred form, the suspension of solid particles of medicament isintroduced into the bottom of the thixotropic suspension.

The present invention affords numerous and important advantages in thetreatment of a condition that involves application of a medicament tothe surface of the mucosa which line the nasal cavities. As will beunderstood from a reading of the example section of the application, thepresent invention provides means for delivering a medicament readily tothe many portions of the nasal cavities where it can perform itspharmacological function. In accordance with the present invention, themedicament remains in contact with the target tissues for relativelylong periods of time, for example, at least about an hour and for eventwo or more hours. Furthermore, the composition of the present inventionis capable of being formulated in a manner such that ingredients whichcause the user discomfort are absent, the composition has satisfactorystability and shelf-life properties, for example, one to two years, andit does not include constituents that are considered to be detrimentalto the environment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a precompression pump which is shownin its rest position and which can be used in applying the compositionof the present invention to the nasal cavities.

FIG. 2 is a cross-sectional view of the pump of FIG. 1 shown in itsactuated position.

DETAILED DESCRIPTION OF THE INVENTION

The water-based composition of the present invention comprises amedicament in the form of solid particles and other pharmaceuticallyacceptable ingredients, that is, materials which are compatible with themedicament, which are not toxic to the body under the conditions of useand which avoid or minimize tissue irritation. As will be appreciatedfrom the description which follows, there is no need to use in thewater-based composition of the present composition a propellant which isa necessary ingredient of aerosol products.

Water is present in the composition in a major amount. Typically, itwill comprise at least about 85 wt. % of the composition and moretypically at least about 90 wt. % of the composition.

The medicament for use in the practice of the present invention is onewhich is capable of treating an abnormal bodily condition by virtue ofits being present on the mucosal surfaces of the nasal cavities.Examples of such a medicament are steroidal and non-steroidalanti-inflammatory agents, beta agonists and bronchodilators. Such amedicament provides the relief of nasal symptoms caused by upperrespiratory tract inflammation and allergic rhinitis.

It is believed that the medicament that will be used most widely in thepractice of the present invention will be an anti-inflammatory steroidsuch as, for example, clomethasone, dexamethasone, fluticasone,prednisolone and triamcinolone acetonide. Such steroidal compounds arerelatively potent drugs which, when applied locally, are highlyeffective with reduced systemic exposure. Triamcinolone acetonide is apreferred medicament for use in the practice of the present invention.

A medicament such as triamcinolone acetonide is substantially waterinsoluble and hydrophobic. For use in the present invention, suchmedicament is present in the composition in the form of solid particlesthat are dispersed in the aqueous phase of the composition. The sizes ofthe particles are such that the medicament is capable of being uniformlydispersed in the composition. For this purpose, the size of theparticles should be no greater than about 50 microns. Preferably theparticles have an average size of about 1 to about 20 microns.

The medicament is present in the composition in a pharmaceuticallyeffective concentration. Such concentration will vary depending on theparticular medicament or mixture of medicaments used, the condition tobe treated and the nature of the individual being treated. For guidelinepurposes, it is recommended that the medicament comprise about 0.001 toabout 2 wt. % of the composition, preferably about 0.01 to about 0.2 wt.% of the composition.

The composition of the present invention contains also apharmaceutically acceptable excipient which is effective in forming athixotropic suspension of the solid particles of medicament comprisingthe composition. The excipient is present in an amount which maintainsthe particles of medicament suspended in the composition during non-useand during spray of the composition into the nasal cavity, and also whenthe composition is deposited on the mucosal surfaces of the nasalcavities. The thixotropic nature of the composition at rest (not subjectto shear) can be described as a gel in which the particles of medicamentare dispersed and suspended substantially uniformly. The viscosity ofthe composition at rest is relatively high, for example, about 400 toabout 1000 cp. As the composition is subjected to shear forces, forexample, upon being subjected to forces involved in its being agitatedbefore spraying, the viscosity of the composition decreases (forexample, to about 50 to about 200 cp) and it flows readily through thespray device and exits therefrom in the form of a fine plume whichinfiltrates and deposits on the mucosal surfaces of at least thefollowing parts of the nose: the anterior regions of the nose (frontalnasal cavities); the frontal sinus; the maxillary sinuses; and theturbinates which overlie the conchas of the nasal cavities. Thus, thethixotropic composition is such that it comprises a freely flowableliquid, and in sprayed form, a fine mist that finds its way to anddeposits on the desired mucosa. In deposited and relatively unstressedform, the composition increases in viscosity and assumes its gel-likeform which includes particles of the medicament suspended therein andwhich resists being cleared from the nasal passages by the inherentmucocillary forces that are present in the nasal cavities. Tests haveshown that amounts of the deposited composition remain on the mucosalsurfaces for relatively long periods of time, for example, at least onehour and even up to two or more hours.

For convenience, the viscosity of the composition at rest is referred toas the "setting viscosity" and the viscosity of a composition which isshaken is referred to as the "shear viscosity". As mentioned above, thesetting viscosity of the composition should be sufficiently high to holdand maintain the particles of medicament dispersed substantiallyuniformly in the composition and to retain for an extended period oftime the composition on the mucosal surfaces on which it is deposited inthe nasal cavities, that is, the composition resists being swept away bythe mucocillary forces which are present in the nasal cavities. Theshear viscosity of the composition is sufficiently low to permit thecomposition to flow freely through the pump orifice and to break up intoa fine mist.

Suitable values for the setting viscosity and for the shear viscosity ofthe composition can be determined for a particular composition, takinginto account also the particular means used to apply the composition tothe nasal cavities. By way of example, a setting viscosity of about 400to about 800 cp is recommended for a composition containing ananti-inflammatory steroid, for example, triamcinolone acetonide. Arecommended shear viscosity for such a composition is about 50 to about200 cp. Viscosity is measured using a Brookfield Synchro-Letricviscometer (Model LVT). The viscosity is measured at 20° C. The settingviscosity is measured after mixing at 30 rpm for 30 seconds. The shearviscosity is measured by mixing at 30 rpm for 30 seconds after mixing ona Burrell wrist-action shaker at full speed for 5 minutes.

Any pharmaceutically acceptable material which is capable of maintainingthe solid particles of medicament dispersed substantially uniformly inthe composition and of imparting to the composition the desiredthixotropic properties can be used. Such material is referred to as a"suspending agent". Examples of suspending agents includecarboxymethylcellulose, veegum, tragacanth, bentonite, methylcellulose,and polyethylene glycols. A preferred suspending agent is a mixture ofmicrocrystalline cellulose and carboxymethylcellulose, the former beingpresent preferably in a major amount, most preferably in an amount ofabout 85 to about 95 wt. %, with the latter constituent comprising about5 to about 15 wt. % of the mixture.

The amount of suspending agent comprising the composition will varydepending on the particular medicament and amount used, the particularsuspending agent used, the nature and amounts of the other ingredientscomprising the composition, and the particular viscosity values that aredesired. Generally speaking, it is believed that the most widely usedcompositions will comprise about 1 to about 5 wt. % of the suspendingagent.

The pharmaceutical composition of the present invention includespreferably other ingredients which impart desired properties to thecomposition.

A composition which contains a medicament which is hydrophobic includespreferably a pharmaceutically acceptable dispersing agent whichfunctions to wet the particles of medicament to facilitate dispersionthereof in the aqueous phase of the composition. The amount ofdispersing agent should be sufficient to wet the hydrophobic particlesof medicament within a short time, for example, about 5 to about 60minutes, as the aqueous dispersion of particles is mixed withconventional mixing equipment. It is preferred to use an amount ofdispersing agent which will not cause foaming of the dispersion duringmixing thereof. It is recommended that the dispersing agent compriseabout 0.001 to about 0.01 wt. % of the composition.

Any dispersing agent which is effective in wetting the particles andwhich is pharmaceutically acceptable can be used. Examples of dispersingagents that can be used are fatty alcohols, esters, and ethers,including, for example, those sold under the trademarks Pluronic,Tergitol, Span, and Tween. It is preferred to use a hydrophilic,non-ionic surfactant. Excellent results have been achieved utilizingsorbitan polyoxyethylene sorbitan monooleate which is available underthe trademark Polysorbate 80.

It is known that various medicaments of the type that can be used in thecomposition of the present invention tend to degrade in the presence ofwater as a result of being oxidized. This can be prevented or deterredby use of an anti-oxidant. Examples of pharmaceutically acceptableanti-oxidants that can be used in the composition include ascorbic acid,sodium ascorbate, sodium bisulfite, sodium thiosulfate, 8-hydroxyquinoline, and N-acetyl cysterine. It is recommended that thecomposition comprise about 0.001 to about 0.01 wt. % of theanti-oxidant.

Also, for stability purposes, the composition should be protected frommicrobial contamination and growth. Examples of pharmaceuticallyacceptable anti-microbial agents that can be used in the compositioninclude quaternary ammonium compounds, for example, benzalkoniumchloride, benzethonium chloride, cetrimide, and cetylpyridiniumchloride; mercurial agents, for example, phenylmercuric nitrate,phenylmercuric acetate, and thimerosal; alcoholic agents, for example,chlorobutanol, phenylethyl alcohol, and benzyl alcohol; antibacterialesters, for example, esters of para-hydroxybenzoic acid; and otheranti-microbial agents such as chlorhexidine, chlorocresol, andpolymyxin. It is recommended that the composition comprise about 0.001to about 1 wt. % of the anti-microbial agent.

As mentioned above, an aspect of the present invention comprises acomposition which is odorless and which contains a mixture ofstabilizing agents which function as an anti-oxidant and as ananti-microbial agent. The mixture comprises a quaternary ammoniumcompound that has anti-microbial properties and a material which isgenerally recognized as a chelating agent. The use in the composition ofthis combination of materials with the medicament, for example,triamcinolone acetonide, results in a highly stable composition that isresistant to oxidative degradation and to the growth of bacteria and thelike. In preferred form, the mixture comprises benzalkonium chloride anddisodium ethylenediamine tetraacetate.

The odorless composition generally will comprise about 0.004 to about0.02 wt. % of the quaternary ammonium compound and about 0.01 to about0.5 wt. % of the chelating agent. By virtue of the use of theaforementioned mixture of compounds, it is not necessary to include inthe composition a material which is considered an anti-oxidant.

The composition of the present invention includes preferably aniso-osmotic agent which functions to prevent irritation of nasal mucosaby the composition. Dextose in anhydrous form is a preferred iso-osmoticagent. Examples of other pharmaceutically acceptable iso-osmotic agentswhich can be used include sodium chloride, dextrose and calciumchloride. It is recommended that the composition comprise up to about 5wt. % of the iso-osmotic agent.

The pH of the composition will vary depending on the particularmedicament used and taking into account biological acceptance and thestability of the medicament. Typically, the pH of the composition willfall within the range of about 4.5 to about 7.5. The preferred pH for acomposition which contains triamcinolone acetonide is about 4.5 to about6, most preferably about 5. Examples of pharmaceutically acceptablematerials which can be used to adjust the pH of the composition includehydrochloric acid and sodium hydroxide.

The composition of the present invention can be prepared in any suitableway. In preferred form, an aqueous suspension of the solid particles ofmedicament and dispersing agent is formed and combined with an aqueoussuspension which contains the suspending agent. The former is preferablyprepared by adding the medicament to an aqueous solution of thedispersing agent and mixing thoroughly. The latter is prepared byacidifying the water (pH about 4.7 to about 5.3) prior to adding thesuspending agent. In particularly preferred form, an aqueous solution ofthe quaternary compound (anti-microbial agent) is added to the aqueoussuspension of medicament, and the other ingredients (for example,iso-osmotic agent, anti-oxidant or chelating agent) are added to thethixotropic suspension. Each of the aforementioned batches ofcomposition is mixed thoroughly before being combined. The preferredmeans of combining the batches of composition is to introduce one of thebatches, preferably the "medicament" batch into the bottom of the otherbatch, for example, by pumping the batch upwardly through the otherbatch. The composition comprising the combined batches is mixedthoroughly. Use of the preferred method of preparation provides anefficient and effective way for formulating a composition that has thesolid particles of medicament substantially uniformly dispersed thereinwhile avoiding problems that are generally associated with thepreparation of water-based pharmaceutical compositions, for example,excessive foaming and non-uniformity of the particle dispersement.

The amount of medicament applied to each of the nasal passages will varydepending on the particular medicament used, the nature of the conditionbeing treated and the nature of the individual being treated. Forguideline purposes, it is suggested that the unit dosage applied to oneof the nasal cavities comprise about 200 to about 450 mcg of themedicament. Use of the preferred form of the composition of the presentinvention provides the advantage that the composition can be appliedeffectively once daily. For such once-a-day dose, it is recommended thatthe amount of medicament, for example, triamcinolone acetonide, appliedto one of the nostrils comprise about 100 to about 130 mcg.

The preferred means for applying the pharmaceutical composition of thepresent invention to the nasal passages is by use of a precompressionpump. A preferred precompression pump is model VP7 manufactured byValois SA of France and marketed in the United States by Valois ofAmerica, 15 Valley Drive, Greenwich, Conn. 06831.

Referring to FIG. 1, the precompression pump 10 has a housing 12 andincludes means such as screw threads 14 for connecting the pump 10 to acontainer of the composition. The housing 12 includes a cylindricalouter wall 16 defining a hollow tube 18, a housing inlet 20 connected toa dip tube 22 through which the liquid enters the pump 10 from thecontainer (not shown), and a cylindrical internal wall 24 positionedbetween the inlet 20 of the inlet tube 22 and the outer wall 16.

A stem 26 extends from the top of the housing 12 and has a bottomsection 28 positioned within the housing hollow tube 18 slidablyengaging the outer wall 16 to form a liquid seal. A center tube 30within the stem connects a stem inlet 32 to a stem outlet 34 throughwhich the liquid is dispensed to an atomizer to generate a spray.

A clapper 36 is slidably positioned within the hollow tube 18 betweenthe stem 26 and the internal wall 24. The clapper 36 has a head section38 which engages the stem inlet 32 to prevent liquid flow therethrough,a shoulder 40, and a bell-shaped bottom section 42 designed to slideover and seal against the housing internal wall 24 when the clapper 36is moved downwardly. A spring 44 between the bottom of the housing 12and the underside of the clapper head section 38 biases the clapper headto engage and seal the stem inlet 32.

The pump 10 operates as follows. In the rest position, as shown in FIG.1, the clapper head 38 seals the stem inlet 32 to prevent liquid flow.The dosage chamber 46 is filled with the composition. It is seen thatthe volume of the dosage chamber 46 is defined by the housing outer wall16, the housing inner wall 24, the clapper 36, and the stem 26. Thedosage volume is controlled by the dimensions of these various elementswhich define the dosage chamber 46.

The action of the user's finger depressing the stem 26 causes the stem26 and clapper 36 to move downwardly. As seen in FIG. 2, the dosechamber 46 is closed by the bottom section 42 of the clapper engagingthe housing internal wall 24. (FIG. 2 shows a side spray nozzle, itbeing understood that this is for illustrative purposes only and thatother forms may be used such as a top spray nozzle.) Further pressurecauses an increase in hydraulic pressure in the composition now isolatedin the dosage chamber 46 relative to the pressure of the compositionwithin the housing internal wall 24. As liquid is essentiallyincompressible, the increased hydraulic pressure of the composition inthe dosage chamber 46 creates a net downward force on the clapper 36.Once this downward force exceeds the upward force on the clapper 36,such as from the spring 44, the clapper moves further downwardly awayfrom the stem 26 to open the stem inlet 32 and allow the liquidcomposition to flow from the dosage chamber 46 to the stem outlet 34 togenerate the spray.

After the spray, when action of the user's finger releases the stem, thespring 44 returns the clapper 36 to engage and seal the inlet 32 andreturn it to its rest position. This movement creates a vacuum whichdraws the composition into the dosage chamber 46 through the housinginlet 20 of the inlet tube 22 for the next dosage.

A precompression pump provides a spray superior to that of conventionalpumps. During normal usage, the precompression pump will deliver a fulldosage of the composition. As previously described, no composition willbe sprayed until the hydraulic pressure of the composition reaches a"threshold" pressure within the pump sufficient to disengage the clapper36 from the stem inlet 32. Once the clapper 36 disengages the stem inlet32, the hydraulic pressure provided by the user's finger forces thepredetermined amount of composition into the stem inlet 32 for spraying.Thus, no spray is released prior to reaching the threshold pressure, andthe entire dosage is released after the threshold pressure is reached.With conventional pumps, an amount less than the full dosage can bereleased if a sufficient amount of force is not applied or if it is notapplied in a proper manner. With the precompression pump, it isextremely difficult to release less than the full dosage when normallyusing the pump.

Another advantage of the precompression pump is that atomization of thespray is ensured. With conventional pumps, sufficient pressure may notbe provided by the user to properly atomize the spray. Theprecompression pump, however, does not release composition until thethreshold pressure is reached, which is designed to be sufficient foratomization.

Furthermore, the precompression pump is less user dependent. Since itwill not spray until the threshold pressure is reached, the force andmethod of depression applied by the user has less of an effect on thespray.

EXAMPLES

The following examples are illustrative of the present invention.

Example 1

A preferred pharmaceutical composition of the present invention isdescribed below.

    ______________________________________                                        COMPONENT            Wt. %    Amount, mg                                      ______________________________________                                        triamcinolone acetonide, USP.                                                                      0.055    9.075                                           micronized topical grade (TAA)                                                mixture of microcrystalline                                                                        2.0      330.00                                          cellulose and carboxymethyl-                                                  cellulose sodium, NF (Avicel CL-611)                                          Polysorbate 80, NF surfactant                                                                      0.004    0.66                                            disodium ethylenediamine                                                                           0.05     8.25                                            tetraacetate, USP                                                             benzalkonium chloride                                                                              0.03     4.95                                            (BZCl) solution, 50 wt. % of BzCl, NF                                         dextrose (anhydrous), USP                                                                          5.0      825.00                                          purified water, USP  92.86    15,322                                          diluted hydrochloric acid, NF                                                                      *        *                                               0.1 N NaOH solution  *        *                                               TOTAL WEIGHT                  16.5 g                                          ______________________________________                                         *Used for pH adjustment.                                                 

The composition is prepared by utilizing a two-container method to mixthe individual ingredients listed above. A large batch of thecomposition is prepared in the manner described below. A 16.5 g portionis extracted from the large batch to fill a spray bottle as describedbelow also.

To a stainless steel kettle equipped with a variable speed sweep mixer,a variable speed agitator, and a fixed speed dispersator, about 500 kgof purified water are added. About 0.4125 kg of disodium ethylenediaminetetraacetate (hereafter "EDTA") and 41.25 kg of dextrose are added tothe water. After the above ingredients are mixed for about 25 minutes,the dispersator and agitator are stopped and the sweep mixer is turnedon. About 0.6 kg of diluted hydrochloric acid ("HCl") solution is addedto the EDTA and dextrose solution. The dispersator is restarted,followed by the addition of about 16.5 kg of a mixture ofmicrocrystalline cellulose and carboxymethylcellulose sodium to theacidified EDTA/dextrose solution. The resulting suspension ishomogenized by continued mixing for about 10 minutes. All mixers arethen stopped for the kettle to be scraped. Homogenization is resumed byusing the sweep mixer and dispersator for about 15 minutes.

To a second stainless steel kettle equipped with a fixed speeddispersator and fixed speed mixer, about 250 kg of purified water areadded. The dispersator and mixer are turned on, followed by the additionof about 0.033 kg of Polysorbate 80 (wetting agent). After about 10minutes of mixing, about 1 liter of the solution is withdrawn. Withcontinued mixing, about 0.45375 kg of triamcinolone acetonide TAA isadded to the kettle containing the dissolved surfactant. The "TAA"container is rinsed with the withdrawn surfactant solution and the rinseis added to the kettle. The TAA suspension is homogenized for about 25minutes using the dispersator and mixer. With the dispersator turnedoff, about 0.2475 kg of the benzalkonium chloride (BzCl) solution areadded and dissolved into the resulting TAA dispersion. The "BzCl"container is rinsed with approximately 1 kg of purified water and therinse is added to the TAA dispersion. The "TAA" dispersion istransferred to the "thixotropic" portion of the composition by pumpingthe TAA dispersion through the bottom outlets of the two kettles. The"TAA" kettle is rinsed with about 10 kg of purified water and the rinseis added to the composition comprising the combined TAA dispersion andthixotropic portion.

The pH of the resulting composition is then determined. The target pH ofpreferred embodiments of the present invention ranges from about4.7-5.3. If needed, the pH is adjusted by adding, most preferably,either: 1) diluted HCl, NF which is diluted further with purified water(20 parts water:1 part diluted HCl, NF); or 2) 0.1N NaOH solution(prepared by dissolving 4 g of sodium hydroxide, NF in purified water,and diluting to 1000 ml). The amount of added HCl or NaOH solution ismeasured, and an amount equal to this is withdrawn from 4.5 kg ofpurified water. After the withdrawn portion is removed, the remainingwater is added to the composition, followed by homogenization using thedispersator for about 2 minutes.

The composition is then transferred to a kettle equipped with afixed-speed mixer. The mixer is set at about 6 rpm and the compositionis mixed thoroughly. The composition has a pH of about 4.8 and at rest(unstressed--not subjected to shear) comprises a gel-like suspension.The TAA particles are uniformly dispersed throughout the composition.

A 16.5 gram portion of the composition is then added to a HDPE round 20ml bottle. Before the bottle is filled, about 0.2u filtered compressedair is blown inside the bottle. The bottle is capped with a meteringpump. The metering pump is a Valois VP7/100S pump having a dip tube, anactuator, an overcap, and a safety clip.

Example 2

Another composition within the scope of the present invention isprepared utilizing the method and ingredients described in Example 1,but with the following changes. In the first mentioned kettle, the EDTA,dextrose, and water are mixed for about 10 minutes measured from thetime that the EDTA and dextrose are added to the water. About 0.53 kgdiluted HCl, NF is added to the EDTA and dextrose solution contained inthe kettle.

Preparation of the "TAA" portion of the composition and transfer thereofto the "thixotropic" portion of the composition is effected as describedin Example 1. During the step of pH adjustment, which takes place afterthe transfer of the "TAA" portion to the "thixotropic" portion, theamount of added HCl or NaOH solution is measured, and an equal amount iswithdrawn from 4.57 kg of purified water. After the withdrawn portion isremoved, the remaining water is added to the composition, followed byhomogenization using the dispersator for about 2 minutes. The pH of thecomposition is about 5. The particles of TAA are dispersed uniformlythroughout the composition. The bottle-filling process is the same asdescribed in Example 1.

The following constitutes a description of examples of how thecomposition of the present invention can be used.

Compositions such as those described in Examples 1 and 2 can be inhalednasally for effective treatment of allergic rhinitis symptoms. Asdescribed in Examples 1 and 2, each of the compositions is packaged in ametered pump spray bottle which holds about 16.5 g of the composition.

A dose of the composition can be delivered to a human patient byspraying the composition into each of the patient's nasal cavities. Fordose delivery, the precompression metering pump (Valois VP7/100S) isplaced in a patient's nostril and is then actuated by the patient,resulting in a spray into the nasal cavity. After initial priming, eachactuation of the pump delivers from the nasal actuator about 100 mg ofcomposition containing about 55 mcg of TAA. Each bottle of compositionwill provide at least about 120 metered doses. For the exemplifiedcompositions, the recommended once-daily dosing for adults and children12 years and older begins at about 220 msg of TAA, equivalent to twosprays in each nostril.

A composition comprising the formulation of Examples 1 and 2 wasadministered to two volunteer patients. Post administration, thepatients were evaluated by positron emission tomography in order todetermine 1) the amount of time it took for the maximum dose of the TAAmedicament to be delivered to various regions of interest within thenasal cavity, and 2) the amount of TAA medicament deposited on theregions of interest over a two hour time period. For purposes of theevaluation, the volume of the head region was segmented into 104distinct regions of interest. Included in the regions of interest arethe following target sites: the frontal cavities, frontal sinus,maxillary sinuses, superior concha, and inferior concha. The results ofevaluation indicate a rapid distribution of the TAA medicament to thetarget regions of the nose.

For one of the volunteers, the maximum amount of the TAA medicamentwhich came in contact with the concha regions was about 65% of the totaldose delivered to the nose and this occurred at about 45 seconds postdose. About 46% of the total dose came in contact with the inferiorconcha and about 19% of the total dose came in contact with the superiorconcha. The amount of TAA medicament in contact with the concha tissuesdeclined with time, until a constant value of about 3.4-4% of the totaldose administered remained in the concha tissues at the final timeperiod. The maximum amount of the TAA medicament which came in contactwith the frontal cavity region was about 41% and this occurred at about45 seconds post dose. The maximum amount of the TAA medicamentcontacting the frontal cavity region slowly declined as a function oftime, maintaining constant levels of about 12% at two hours post-dose.Based upon this information, the frontal cavity is considered a targettissue since the deposited composition is maintained as a reserve orback-up supply of the medicament. The slow migration of the viscouscomposition back over the concha tissues via mucocillary clearancesuggests that TAA medicament is continuously bathing the target tissues,thus accounting for the efficacy of the preferred once-daily dosing.Interestingly, the drug appears to enter into both the maxillary andfrontal sinuses. The data suggest that the particles of the medicamentare carried into the sinuses due to the turbulent airflow during nasalinhalation. The maximum amount deposited was approximately 3.5% and 3.9%of the dose into the frontal and maxillary sinuses respectively, andthis occurred within about 30 seconds after post dose. The data indicatethat the TAA medicament is cleared from the frontal sinus within 1 hourand that approximately 1% of the medicament is still present at the twohour acquisition sampling time in the maxillary sinuses.

For the other volunteer, the maximum amount of the drug which came incontact with the concha regions was about 53% of the total dosedelivered to the nose, about 25% associated with the superior concha andabout 75% associated with the inferior concha. The maximum amount of theTAA medicament which came in contact with the superior concha regionoccurred at about 25 seconds post dose and for the inferior concharegion at about 3.5 minutes. This data suggests that the TAA medicamentis moving into the concha region from the frontal cavity area. At abouttwo hours post-administration, about 6-8% of the administered dose stillremained in contact with the concha regions, with the medicament slowlybeing cleared from this target site.

The maximum amount of the TAA medicament which came in contact with thefrontal cavity was about 55% of the total dose delivered to the nose andthis occurred within about 30 seconds post dose. The medicament appearedto leave the nasal cavity slowly with approximately 22% of the dosestill resident after two hours. A small percentage of the administereddose of the TAA medicament came into contact with the maxillary andfrontal sinuses. The maximum amount was deposited within about 30seconds post dose, with values around 3.5% for the frontal sinus andabout 2% for the maxillary sinus. These values remained relativelyconstant, with approximately 0.5% to 1% of the dose still remaining inthe sinuses after two hours.

The evaluation included also a determination of the percentage of theTAA medicament remaining on the target sites two hours after it wasadministered to each of the patients. This percentage was determined bydividing the amount remaining in each region of interest by the totalamount remaining in the 104 regions of interest. The results from thisevaluation indicate that greater than 85% of the dose was directlydeposited on the target sites, including the frontal cavity, frontalsinus, maxillary sinuses, superior concha, and inferior concha.

For the first of the volunteers discussed above, the results indicatethat about 47.9% of the total TAA medicament remained deposited in thefrontal cavity two hours after the drug was administered. The percentageof the total medicament deposited in the inferior concha region twohours post administration (about 27.8%), when combined with the superiorconcha region deposited amount (about 8.6%), accounted for about 36.4%of the amount remaining of the dose administered to the principal targetregion of the nose. Over a two-hour period of time, about 1.2% of thedose was deposited on the frontal sinus while about 3% of the dose wasdeposited in the maxillary sinus region. Summing the percentages of theadministered drug remaining on the target sites two hours after themedicament was administered indicates that about 88.5% of the doseadministered was deposited directly onto target tissues over thetwo-hour serial sampling period.

For the second of the volunteers discussed above, the results indicatethat about 52.2% of the dose administered remained deposited in thefrontal cavity two hours post-drug administration. About 23.5% of thedose remained deposited on the inferior concha and about 6.9% of thedose remained deposited on the superior concha. Total percentage of thedose remaining deposited on the concha region was about 30.4% of theoverall dose delivered. Values for the frontal and maxillary sinuseswere about 1.6% and about 1.4% of the dose administered, respectively.Summing the percentages of the administered drug remaining on the targetsites two hours after the drug was administered indicates that about85.6% of the dose administered was deposited directly onto targettissues over the two hour serial sampling period.

It should be appreciated that the present invention provides effectiveand improved means for relieving patients from unsettling abnormalbodily conditions.

I claim:
 1. An aqueous pharmaceutical composition which is capable ofbeing sprayed into the nasal cavity of an individual and whichcomprises: (A) a pharmaceutically effective amount of solid particles oftriamcinolone acetonide which is effective in treating an abnormalbodily condition by virtue of its being present on the mucosal surfacesof the nasal cavity; and (B) a suspending agent in an amount effectiveto maintain said particles dispersed uniformly in the composition and toimpart to the composition the following thixotropic properties: (i) theviscosity of the composition in unsheared form is relatively high, withthe composition being a gel having said particles suspended therein;(ii) as the composition is subjected to shear (shaken) in preparationfor spraying, the viscosity of the composition becomes relatively lowand such that the composition in the form of a mist flows readily intothe nasal passages for deposit on the mucosal surfaces of the nasalcavity; and (iii) in deposited form on the mucosal surfaces, theviscosity of the composition is relatively high and such that it resistsbeing cleared from the mucosal surfaces by the inherent mucocillaryforces which are present in the nasal cavity.
 2. The composition ofclaim 1 wherein said composition includes microcrystalline cellulose andcarboxymethyl cellulose sodium and a chelating agent.
 3. The compositionof claim 2 wherein said chelating agent is disodium ethylene diaminetetraacetate.
 4. The composition of claim 2 wherein said compositionincludes dextrose.
 5. An aqueous pharmaceutical composition which iscapable of being sprayed into the nasal cavity of an individual, whichis odorless, propellant-free, and has a pH of about 4.5 to about 7.5,and which comprises: (A) at least about 85 wt. % of water; (B) about0.001 to about 2 wt. % of solid particles of triamcinolone acetonidemedicament; (C) about 1 to about 5 wt. % of a suspending agentcomprising a mixture of about 85 to 95 wt. % of microcrystallinecellulose and about 5 to about 15 wt. % of carboxymethyl cellulose basedon the weight of the mixture, the amount of suspending agent beingeffective to maintain said solid particles dispersed uniformly in thecomposition and to impart to the composition the following thixotropicproperties: (i) the viscosity of the composition in unsheared form isabout 400 to about 800 cp; (ii) as the composition is subjected to shear(shaken) in preparation for spraying, the viscosity of the compositionis about 50 to about 200 cp and such that the composition in the form ofa mist flows readily into the nasal passages for deposit on the mucosalsurfaces of the nasal cavity; and (iii) in deposited form on the mucosalsurfaces, the viscosity of the composition is about 400 to about 800 cpand such that it resists being cleared from the mucosal surfaces by theinherent mucocillary forces which are present in the nasal cavity; and(D) about 0.004 to about 0.02 wt. % of a quaternary ammonium compoundthat has anti-microbial properties; and (E) about 0.01 to about 0.5 wt.% of a chelating agent.
 6. A composition according to claim 5 whereinsaid quaternary ammonium compound is benzalkonium chloride and saidchelating agent is disodium ethylenediamine tetraacetate.
 7. Acomposition according to claim 5 having about 0.001 to about 0.01 wt. %of dispersing agent which is effective in wetting the particles ofmedicament.
 8. A composition according to claim 7 wherein saiddispersing agent is Polysorbate 80™.
 9. A composition according to claim5 including dextrose.
 10. The composition of claim 5 wherein said solidparticles of medicament have an average size of about 1 to about 20microns.
 11. A product comprising an aqueous pharmaceutical compositioncomprising a medicament in the form of solid particles of triamcinoloneacetonide, a dispersing agent for wetting said particles, and asuspending agent for maintaining said particles substantially uniformlydispersed in the composition and for imparting to the compositionthixotropic properties, prepared by a process comprising: (A) providinga suspension of said particles and said dispersing agent; (B) providinga thixotropic aqueous suspension comprising said suspending agent; and(C) combining each of the suspensions by introducing one of thesuspensions into the bottom of the other suspension.
 12. The product ofclaim 11 wherein the suspensions are combined by introducing thesuspension of (A) into the bottom of the suspension of (B).
 13. Theproduct of claim 12 wherein the suspensions are combined by introducingthe suspension of (A) into the bottom of the suspension of (B) bypumping said suspension of (A) into the bottom of said suspension of(B).
 14. The product of claim 11 wherein an aqueous solution of aquaternary compound is added to the suspension of (A) and an iso-osmoticagent and a chelating agent are added to the suspension of (B) prior tocombining the suspension of (A) and (B).
 15. A method for preparing anaqueous pharmaceutical composition comprising a medicament in the formof solid particles of triamcinolone acetonide, a dispersing agent forwetting said particles, and a suspending agent for maintaining saidparticles substantially uniformly dispersed in the composition and forimparting to the composition thixotropic properties, said methodcomprising: (A) providing an aqueous suspension of said particles andsaid dispersing agent; (B) providing a thixotropic aqueous suspensioncomprising said suspending agent; and (C) combining each of thesuspensions by introducing one of the suspensions into the bottom of theother suspension.
 16. The method of claim 15 wherein said dispersingagent is 80™.
 17. The method of claim 15 wherein said suspending agentis a mixture of microcrystalline cellulose and carboxymethylcellulosesodium.
 18. A method according to claim 15 wherein the suspension ofparticles is introduced into the bottom of the thixotropic suspension.19. A method according to claim 15 wherein said dispersing agent isPolysorbate 80™ and wherein said suspension of (A) further comprises aquaternary ammonium anti-microbial agent and wherein the suspension of(B) further comprises a chelating agent and an anti-osmotic agent.
 20. Amethod according to claim 19 wherein the antimicrobial agent consistsessentially of benzalkonium chloride, the chelating agent consistsessentially of EDTA and the anti-osmotic agent consists essentially ofdextrose.
 21. A method for treating allergic rhinitis in an individualcomprising applying to the mucosal surfaces of the nasal cavities of anindividual a composition according to claim 5 by spraying a dose of thecomposition into each of the nasal cavities of the individual, said dosecontaining a pharmaceutically effective amount of said medicament anddepositing pharmaceutically effective amounts of the medicament on eachof the mucosal surfaces of the anterior regions of the nose, the frontalsinus and the maxillary sinuses and on each of the mucosal surfaceswhich overlie the turbinates covering the conchas and such thatpharmaceutically effective amounts of the medicament are retained oneach of said mucosal surfaces for at least about an hour.
 22. A methodaccording to claim 21 wherein said quaternary ammonium compound isbenzalkonium chloride, and said chelating agent is disodiumethylenediamine tetraacetate.
 23. A method according to claim 21 whereinthe composition which is applied to said surfaces includes about 0.001to about 0.01 wt. % of dispersing agent which is effective in wettingthe particles of medicament.
 24. A method according to claim 23 whereinsaid dispersing agent is Polysorbate 80™.
 25. A method according toclaim 21 wherein the dose of composition applied to each of the nasalcavities comprises about 200 to about 450 mcg of medicament.
 26. Amethod according to claim 21 wherein said composition is applied oncedaily to each of the nasal cavities of the individual in an amount whichincludes about 100 to about 130 mcg of said medicament.
 27. A methodaccording to claim 26 wherein said composition is applied by use of aprecompression pump.
 28. The method according to claim 26 wherein saidcomposition comprises triamcinolone acetonide, a mixture ofmicrocrystalline cellulose and carboxymethyl cellulose sodium,Polysorbate 80™, disodium ethylenediamine tetraacetate, benzalkoniumchloride, dextrose and purified water.
 29. A method of treatmentaccording to claim 21 wherein said allergic rhinitis is seasonalallergic rhinitis.
 30. A method of treatment according to claim 21wherein said allergic rhinitis is perennial allergic rhinitis.
 31. Amethod of treatment according to claim 21 wherein at least about 47% ofthe total medicament remains deposited in the frontal cavity of theindividual two hours after administration.
 32. A method of treatmentaccording to claim 21 wherein at least about 23% of the total medicamentremains deposited in the inferior concha region of the individual twohours after administration.
 33. A method of treatment according to claim21 wherein at least about 6% of the total medicament remains depositedin the superior concha region of the individual two hours afteradministration.
 34. A method for applying solid particles oftriamcinolone acetonide to the mucosal surfaces of the nasal cavitiescomprising spraying a dose of an aqueous pharmaceutical compositioncontaining said medicament into each of the nasal cavities, said dosecontaining a pharmaceutically effective amount of triamcinoloneacetonide, said composition including also a suspending agent in anamount which is effective in maintaining said particles disperseduniformly in the composition and in imparting to the compositionthixotropic properties such that pharmaceutically effective amounts oftriamcinolone acetonide are deposited on each of the mucosal surfaces ofthe anterior regions of the nose, the frontal sinus and the maxillarysinuses, and on each of the mucosal surfaces which overlie theturbinates covering the conchas and such that portions of said amountsare retained on each of said mucosal surfaces for at least about anhour.
 35. A method according to claim 34 wherein the viscosity of thecomposition in unsheared form is about 400 to about 1000 centipoises andwherein the viscosity of the composition when shaken is about 50 toabout 200 centipoises.